Macrophages play a central role in orchestrating inflammation and immune responses, with their polarization states (M1 or M2) exhibiting both pro- and anti-inflammatory, as well as anti-cancer functions. Inducible nitric oxide synthase (iNOS) plays a pivotal role in immune regulation through its impact on macrophage polarization. As a hallmark of M1 macrophages, iNOS drives pro-inflammatory responses, while its suppression favors anti-inflammatory M2 phenotypes. This dual role as both a biomarker and regulatory hub positions iNOS as a promising therapeutic target across diverse disease states. This review examines the roles of iNOS modulation in macrophage polarization across various disease models. Both synthetic and natural iNOS regulators have been shown to modulate iNOS activity, thereby reprogramming macrophages toward either inflammatory or reparative phenotypes. We categorize these regulators into those that directly inhibit enzymatic activity and those that indirectly modulate through signaling pathways. Additionally, recent preclinical and clinical studies on iNOS inhibitors are summarized, highlighting their therapeutic potential in inflammatory, metabolic, and oncologic diseases. Taken together, the evidence underscores the therapeutic relevance of iNOS regulation as a strategy to reprogram macrophage plasticity in disease-specific immune microenvironments.

The extract of Paspalum thunbergii, a native perennial herb in Korea belonging to the rice family, was investigated for its anti-inflammatory activity and the underlying mechanisms driving its effects. Fifteen chemical components of the P. thunbergii extract, including rosmarinic acid and isoquercitrin, were identified using LC-MS. The extract showed antioxidative activity through DPPH and ABTS cation radical scavenging activity. The P. thunbergii extract significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. The extract inhibited the expression of lipopolysaccharide-induced iNOS and COX-2, which are inflammation-related enzymes. To explore the underlying anti-inflammatory mechanism, the expression levels of signal proteins related to MAPK, NF-κB, JAK/STAT, and Wnt/β-catenin signaling were measured. As a result, the P. thunbergii extract inhibited the expression of p-p38, and p-JNK increased by LPS in RAW 264.7 cells. Additionally, it decreased the expression of LPS-induced p-IKKβ and p-NF-κB p65 and prevented the migration of p-NF-κB into the nucleus caused by LPS. Notably, p-JAK1, p-STAT3, Wnt 3α, β-catenin, and p-GSK-3β protein expressions were also inhibited. Therefore, the prominent anti-inflammatory activity of the P. thunbergii extract may be via the MAPK, NF-κB, JAK/STAT, Wnt/β-catenin signal pathway.

Natural products have a long history of use as valuable therapeutic resources, and continue to provide structurally diverse bioactive compounds for pharmaceutical, biomedical, nutraceutical, and cosmetic applications